Review Article
Journal of Cerebral Blood Flow & Metabolism (2001) 21, 755–778; doi:10.1097/00004647-200107000-00001
Stroke Genomics: Approaches to Identify, Validate, and Understand Ischemic Stroke Gene Expression
Simon J Read*, Andrew A Parsons*, David C Harrison*, Karen Philpott*, Karen Kabnick†, Shawn O'Brien‡, Steven Clark‡, Mary Brawner‡, Stewart Bates‡, Israel Gloger‡, Jeffrey J Legos§ and Frank C Barone§
- *Neurology Center of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, U.K., and King of Prussia, Pennsylvania, U.S.A.
- †Neurology Center of Excellence for Bioinformatics, GlaxoSmithKline, Harlow, U.K., and King of Prussia, Pennsylvania, U.S.A.
- ‡Neurology Center of Excellence for Genetics Research, GlaxoSmithKline, Harlow, U.K., and King of Prussia, Pennsylvania, U.S.A.
- §Neurology Center of Excellence for High Throughput Biology, GlaxoSmithKline, Harlow, U.K., and King of Prussia, Pennsylvania, U.S.A.
Correspondence: Dr. Simon J. Read, Neurology, HW2515, GlaxoSmithKline, New Frontiers Science Park North, Harlow CM19 5AW, U.K.; Dr. Frank C. Brone, High Throughput Biology, UW2521, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, U.S.A.
Received 16 April 2001; Revised 19 April 2001; Accepted 19 April 2001.
Abstract
Sequencing of the human genome is nearing completion and biologists, molecular biologists, and bioinformatics specialists have teamed up to develop global genomic technologies to help decipher the complex nature of pathophysiologic gene function. This review will focus on differential gene expression in ischemic stroke. It will discuss inheritance in the broader stroke population, how experimental models of spontaneous stroke might be applied to humans to identify chromosomal loci of increased risk and ischemic sensitivity, and also how the gene expression induced by stroke is related to the poststroke processes of brain injury, repair, and recovery. In addition, we discuss and summarise the literature of experimental stroke genomics and compare several approaches of differential gene expression analyzes. These include a comparison of representational difference analysis we have provided using an experimental stroke model that is representative of stroke evolution observed most often in man, and a summary of available data on stroke differential gene expression. Issues regarding validation of potential genes as stroke targets, the verification of message translation to protein products, the relevance of the expression of neuroprotective and neurodestructive genes and their specific timings, and the emerging problems of handling novel genes that may be discovered during differential gene expression analyses will also be addressed.
Keywords:
Differential display, Gene expression, MCAO, Microarray gridding, Neuroprotective genes, Neurodestructive genes, Protein, Representative differential analysis, Stroke, Stroke in evolution, Suppressive subtractive hybridization, Target validation, Transcription, Translation
Abbreviations:
ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; DWI, diffusion weighted imaging; IEGS, immediate early genes; MCA, middle cerebral artery; MCAO, middle cerebral artery occlusion; MEALS, mitochondrial encephalopathy-lactic acidosis and strokelike syndrome; MRI, magnetic resonance imaging; pMCAO, permanent MACO; PWI, perfusion-weighted imaging; RDA, representational difference analysis; SHR, spontaneously hypertensive rat; WKY, Wistar-Kyoto rats
